The aims of this study were the following: (1) to estimate the prevalence of hepatitis C virus (HCV) antibody (anti-HCV) in a population-based survey of French residents not selected for risk factors; (2) to investigate the association between anti-HCV seropositivity, viremia, the infecting HCV genotype, and the alanine transaminase (ALT) level; and (3) to identify risk factors for HCV infection by a nested case control study within this survey sample. The anti-HCV seroprevalence survey was performed in 6,283 volunteers (20- to 59-years-old) randomly selected from 45,377 consecutive individuals undergoing routine medical checkup in social security medical centers covering 4 of the 22 “regions” of France. Seventy-two volunteers were anti-HCV positive, a crude prevalence of 1.15%. Fifty percent of these positive volunteers also had an abnormal ALT level and 81% were HCV-RNA positive by polymerase chain reaction (PCR). The prevalence weighted for age, sex, and place of residence was 1.05% (95% CI: 0.75-1.34). The weighted prevalence was lower among men > 40-years-old (0.5%; 95% CI: 0.1-1.0) and was close to 1% in all other age and sex groups. Prevalence was inversely correlated with socioprofessional status with the highest rate being found among those with no paid employment (2.2%; 95% CI: 1.3-3.0). The HCV prevalence (1.7%; 95% CI: 1.0-2.3) was highest in southeastern France. Seventy-eight percent of positive intervenous (I.V.) drug abusers were infected with HCV genotypes 1a or 3, whereas 80% of the transfusion-associated cases were infected by HCV genotypes 1b or 2a. Only three variables were significantly associated with HCV seropositivity in multivariate analysis: I.V. drug abuse (21 cases, 14 men all < 40-years-old), previous transfusion (22 cases, 18 women), and not having paid employment. Although routes of transmission other than I.V. drug abuse and transfusion may not be formally excluded they were not found to be statistically significant. Hepatitis C appears to be a major public health concern in France. A more active screening policy may be required because only 17 of 72 cases (24%) were aware of their HCV seropositivity before enrollment in the study.